Terphenly derivatives, preparation thereof, compositions containing same

ABSTRACT

The invention relates to terphenyl derivatives of formula:  
                 
and to their preparation and to the pharmaceutical compositions comprising them.  
     These compounds exhibit an antagonist activity with respect to CB 1  cannabinoid receptors.

The present invention relates to terphenyl derivatives, to theirpreparation and to pharmaceutical compositions comprising them.

Accordingly the present invention provides compounds of formula:

in which:

R₁ represents hydrogen or a (C₁-C₄)alkyl;

R₂ represents: a (C₃-C₇) alkyl group,

-   -   an indan-1-yl or 1,2,3,4-tetrahydronaphthalen-1-yl group, said        groups being unsubstituted or substituted by a halogen atom        and/or a methyl group;    -   a saturated, single-nitrogen heterocyclic radical of 5 to 7        atoms, the nitrogen atom being substituted by a (C₁-C₄)alkyl,        benzyl, (C₁-C₃)alkoxycarbonyl or (C₁-C₄)alkanoyl group;    -   a group NR₉R₁₀;    -   a group (CH₂)_(n)R₁₁, CH(CH₃)R₁₁, (CH₂)_(m)N(CH₃)R₁₁;    -   a C₃-C₁₂ nonaromatic carbocyclic radical, unsubstituted or        substituted one or more times by a methyl group;

or R₁ and R₂ together with the nitrogen atom to which they are attachedform either a piperazin-1-yl radical substituted in position 4 by aphenyl or benzyl group, or a piperidin-1-yl radical disubstituted inposition 4 by a phenyl or benzyl group and by a (C₁-C₄)alkyl or(C₁-C₃)alkanoyl group; the phenyl or benzyl group substituents on thepiperazin-1-yl radical or the piperidin-1-yl radical being unsubstitutedor substituted by a halogen atom and/or a methyl group;

R₃, R₄, R₅, R₆, R₇ and R₈ represent each independently of one another ahydrogen or halogen atom or a (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl group;

R₉ and R₁₀ together with the nitrogen atom to which they are attachedform a saturated or unsaturated heterocyclic radical of 5 to 10 atomscontaining or not containing a second heteroatom selected from O and N,said radical being unsubstituted or substituted one or more times by a(C₁-C₄)alkyl, hydroxyl or (C₁-C₄)alkoxy group;

R₁₁ represents: a phenyl which is unsubstituted or substituted by one ormore substituents selected from a halogen atom and a methyl group;

-   -   a heteroaryl radical of 6 to 10 atoms containing one or more        nitrogen atoms;

n represents 1, 2 or 3;

m represents 0, 2 or 3;

and their salts, their solvates and their hydrates.

The compounds of formula (I) may exist in the form of bases or ofaddition salts with acids. These salts are advantageously prepared withpharmaceutically acceptable acids, although the salts of other acidsuseful, for example, for purifying or isolating compounds of formula (I)also form part of the invention.

An alkyl group is a linear or branched radical such as, in particular:methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, n-hexyl or isohexyl, the methyl group being preferred for a(C₁-C₄)alkyl and the tert-butyl, 2-methylbut-2-yl and3,3-dimethylbut-2-yl groups being preferred for a (C₁-C₆)alkyl.

A (C₁-C₆)alkoxy group is a linear or branched radical containing 1 to 6carbon atoms, the methoxy group being preferred.

A halogen atom is a fluorine, chlorine, bromine or iodine atom,fluorine, chlorine or bromine atoms being preferred.

The C₃-C₁₂ nonaromatic carbocyclic radicals comprise monocyclic orpolycyclic, fused or bridged radicals. The monocyclic radicals includecycloalkyls, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl, cyclohexyl and cyclopentyl beingpreferred. The fused dicyclic or tricyclic radicals, bridged or inspiran form, include for example the radicals norbornyl, bornyl,isobornyl, noradamantyl, adamantyl, spiro[5.5]undecanyl andbicyclo[2.2.1]heptanyl, with spiro[5.5]undecanyl andbicyclo[2.2.1]heptanyl being preferred.

A saturated or unsaturated heterocyclic radical of 5 to 10 atoms,containing or not containing a second heteroatom such as O or N,embraces radicals such as morpholin-4-yl, piperidin-1-yl,piperazin-1-yl, pyrrolidin-1-yl, 3,6-dihydropyridin-1-yl andoctahydrocyclopenta[c]pyrrol-2-yl, preference being given to theradicals pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl.

Among the compounds according to the invention preference is given tothe compounds of formula (I) in which:

R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group;

R₂ represents a group NR₉R₁₀ or a nonaromatic C₃-C₁₂ carbocyclic radicalwhich is unsubstituted or substituted one or more times by a methylgroup;

R₃, R₄, R₅, R₆, R₇ and R₈ represent each independently of one another ahydrogen or halogen atom or a (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl group;

R₉ and R₁₀ together with the nitrogen atom to which they are attachedform a saturated or unsaturated heterocyclic radical of 5 to 10 atoms,containing or not containing a second heteroatom selected from O and N,said radical being unsubstituted or substituted one or more times by a(C₁-C₆)alkyl group;

and their salts, their solvates and their hydrates.

Among the compounds provided by the invention mention may be made of thepreferred compounds which are defined by the following values for thesubstituents:

R₁ represents a hydrogen atom; and/or

R₂ represents a group selected from piperidin-1-yl, pyrrolidin-1-yl,cyclohexyl, spiro[5.5]undecanyl and1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl; and/or

at least one of the substituents R₃, R₄ and R₅ represents a halogen atomor a trifluoromethyl group; and/or

at least one of the substituents R₆, R₇ and R₈ represents a halogenatom.

The present invention further provides a process for preparing compoundsof formula (I). This process is characterized in that a functionalderivative of terphenylic acid of formula:

in which R₃, R₄, R₅, R₆, R₇ and R₈ are as defined for (I) is treatedwith an amine of formula HNR₁R₂ (III) in which R₁ and R₂ are as definedfor (I). Optionally the compound thus obtained is converted into one ofits salts and/or solvates.

As a functional derivative of the acid (II) it is possible to use theacid chloride, the anhydride, a mixed anhydride, a C₁-C₄ alkyl ester inwhich the alkyl is linear or branched, an activated ester, for example,the p-nitrophenyl ester or the appropriately activated free acid,activated for example with N,N-dicyclohexylcarbodiimide or withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP).

Thus in the process according to the invention the chloride ofpyrazol-3-carboxylic acid, obtained by reacting thionyl chloride withthe acid of formula (II), can be reacted with an amine HNR₁R₂ in aninert solvent such as a chlorinated solvent (dichloromethane,dichloroethane, or chloroform, for example), an ether (tetrahydrofuranor dioxane, for example) or an amide (N,N-dimethylformamide, forexample) under an inert atmosphere at a temperature of between 0° C. andthe ambient temperature in the presence of a tertiary amine such astriethylamine, N-methylmorpholine or pyridine.

One variant consists in preparing the mixed anhydride of the acid offormula (II) by reacting ethyl chloroformate with the acid of formula(II) in the presence of a base such as triethylamine and in reactingsaid mixed anhydride with an amine HNR₁R₂ in a solvent such asdichloromethane under an inert atmosphere at ambient temperature in thepresence of a base such as triethylamine.

The acids of formula (II) can be prepared in accordance with thefollowing scheme:

In step a₁ the reaction of the organoborate of formula (IV) with anester of 4-hydroxy-3-iodobenzoic acid is carried out by the method ofFarmaco Ed. Sci., 1958, 13, 121, using the conditions described bySuzuki in Helv. Chem. Acta, 1992, 75, 855.

In step b₁, the product is reacted with triflic anhydride ((Tf)₂O) inpyridine in order to prepare the compound of formula (VI). That compoundis coupled in step c₁ with an organoborate of formula (VII) under theconditions described in J. Org. Chem., 1992, 57, 379.

The terphenyl ester thus formed is subsequently hydrolyzed by knownmethods, in the presence of potassium hydroxide, for example, to givethe acid of formula (II).

Compounds of formula (II) in which all of the substituents R₃ to R₈ arehydrogen are described in patent U.S. Pat. No. 4,916,145 and in thepublication by T. Sato et al., Bull. Chem. Soc. Jap., 1971, 44(9),2484-2490; the compounds of formula (II) in which the substituents R₃and R₆ are simultaneously a 3-methoxy, a 4-methoxy or a 3-fluoro, theother substituents R₄, R₅, R₆, R₇ and R₈ being hydrogen, are describedin patent U.S. Pat. No. 4,916,145; the compounds of formula (II) inwhich the substituents R₃, R₄ and R₆, R₇ are simultaneously3,4-dimethoxy and the substituents R₅ and R₈ are hydrogen are describedin the publication by E. Brenna, J. Chem. Soc. Perkin Trans. I, 1998,901-904.

The other acids of formula (II) and their esters of formula (VIII) arenew and constitute a final aspect of the invention. Accordingly, thepresent invention also provides compounds of formula:

in which R₃, R₄, R₅, R₆, R₇ and R₈ are as defined for (I) and Rrepresents a hydrogen atom or a (C₁-C₄)alkyl group, on condition thatR₃, R₄, R₅, R₆, R₇ and R₈ are not simultaneously hydrogen, and oncondition that, when R₄, R₅, R₇ and R₈ represent hydrogen, R₃ and R₆ donot simultaneously represent a fluorine atom in meta position, or amethoxy group in meta or para position, and on condition that when R₅and R₈ represent hydrogen R₃, R₄ and R₅, R₆ do not simultaneouslyrepresent 3,4-dimethoxy groups.

More particularly preference is given to the compounds of formula (IIa)in which:

R₃ is in position 4 and represents a halogen atom or a trifluoromethylgroup;

R₆ is in position 2 and represents a hydrogen or halogen atom;

R₇ is in position 4 and represents a halogen atom;

R₄, R₅ and R₈ are hydrogen.

The amines HNR₁R₂ (III) are known or are prepared by known methods; byway of example mention may be made of: Chem. Ber. 1986, 119, 1413-1423.

The compounds of the formula (I) possess very good in vitro affinity(IC₅₀≦10⁻⁷ M) for cannabinoid receptors CB₁, under the experimentalconditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994,350, 240-244).

The antagonist nature of the compounds of formula (I) is demonstrated bythe results obtained in adenylate cyclase inhibition models as describedin M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278,871-878.

The toxicity of the compounds of formula (I) is compatible with theiruse as a medicinal product.

In accordance with another of its aspects the present invention providesfor the use of a compound of formula (I), or of one of itspharmaceutically acceptable salts, solvates or hydrates, for preparingmedicinal products intended for treating diseases involving CB₁cannabinoid receptors.

For example and without limitation, the compounds of formula (I) areuseful as psychotropic medicinal products, particularly for treatingpsychiatric disorders, including anxiety, depression, mood disorders,insomnia, disorders involving delirium, obsessive disorders, psychosesin general, schizophrenia, and also for treating disorders linked to theuse of psychotropic substances, particularly in the case of substanceabuse and/or substance addiction, including alcohol addiction andnicotine addiction.

The compounds of formula (I) according to the invention can be used asmedicinal products for treating migraine, stress, diseases ofpsychosomatic origin, panic attacks, epilepsy, locomotor disorders,especially dyskinesias or Parkinson's disease, shaking and dystonia.

The compounds of formula (I) according to the invention can also be usedas medicinal products in treating memory disorders, cognitive disorders,especially in treating senile dementia and Alzheimer's disease, and alsoin the treatment of attention disorders or vigilance disorders. Inaddition the compounds of formula (I) may be useful as neuroprotectiveagents, in treating ischemia and cranial traumas and in treatingneurodegenerative diseases, including chorea, Huntingdon's chorea andTourette's syndrome.

The compounds of formula (I) according to the invention may be used asmedicinal products in treating pain: neuropathic pain, peripheral acutepain, and chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention may be used asmedicinal products in treating appetite disorders, cravings (for sugars,carbohydrates, drugs, alcohols or any appetizing substance) and/oreating disorders, especially as anorexigenic agents or for treatingobesity or bulimia, and also for treating type II diabetes ornon-insulin-dependent diabetes. Moreover, the compounds of formula (I)according to the invention may be used as medicinal products in treatinggastrointestinal disorders, diarrheic disorders, ulcers, vomiting,urinary and bladder disorders, disorders of endocrine origin,cardiovascular disorders, hypotension, hemorrhagic shock, septic shock,chronic cirrhosis of the liver, asthma, Raynaud's syndrome, glaucoma,fertility disorders, inflammatory phenomena, immune system diseases,especially autoimmune and neuroinflammatory diseases such as rheumatoidarthritis, reactional arthritis, diseases resulting in demyelinization,multiple sclerosis, infectious and viral diseases such as encephalitis,cerebrovascular accidents, and as medicinal products for anticancerchemotherapy and for treating Guillian-Barré syndrome.

According to the present invention the compounds of formula (I) areespecially useful for treating psychotic disorders, especiallyschizophrenia; for treating appetite disorders and obesity; for treatingmemory and cognitive disorders; for treating alcohol addiction andnicotine addiction, in other words for alcohol withdrawal and tobaccowithdrawal.

According to one of its aspects the present invention relates to the useof a compound of the formula (I), of its pharmaceutically acceptablesalts and of their solvates or hydrates for treating the disorders anddiseases indicated above.

The compound according to the invention is generally administered as adosage unit.

Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active principle is mixed with apharmaceutical excipient.

Thus, according to another of its aspects, the present inventionprovides pharmaceutical compositions comprising as active principle acompound of formula (I), one of its pharmaceutically acceptable salts orone of their solvates.

The compound of formula (I) above and the pharmaceutically acceptablesolvates or salts thereof can be used at daily doses of from 0.01 to 100mg per kg of body weight of the mammal to be treated, preferably atdaily doses of from 0.02 to 50 mg/kg. In humans the dose can varypreferably from 0.05 to 4000 mg per day, more particularly from 0.1 to1000 mg per day, depending on the age of the individual to be treated oron the type of treatment, namely prophylactic or curative. Althoughthese doses are examples of average situations, there may be particularcases where higher or lower doses are appropriate, and such doses alsobelong to the invention. In accordance with usual practice the dosewhich is appropriate for each patient is determined by the physicianaccording to the method of administration and the age, weight andresponse of said patient.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhaled, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active principle can beadministered in unit administration form, as a mixture with conventionalpharmaceutical vehicles, to animals and to humans. The suitable unitadministration forms comprise oral-route forms such as tablets, gelcapsules, powders, granules and oral solutions or suspensions,sublingual and buccal administration forms, aerosols, topicaladministration forms, implants, subcutaneous, intramuscular,intravenous, intranasal or intraocular administration forms and rectaladministration forms.

In the pharmaceutical compositions of the present invention the activeprinciple is generally formulated in dosage units containing from 0.05to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200mg of said active principle per dosage unit for daily administrations.

In the present description the following abbreviations are used:

-   DCM: dichloromethane-   DMF: dimethylformamide-   AcOEt: ethyl acetate-   AT: ambient temperature-   m.p.: melting point.

The compounds according to the invention are analyzed by LC/UV/MScoupling (liquid chromatography/UV detection/mass spectrometry).Measurements are made of the molecular peak (M⁺) and the retention time(t) in minutes.

An Xterra Waters® MS C18 column is used, sold by Waters, measuring2.1×30 mm, 3.5 μm, at ambient temperature, with a flow rate of 1mL/minute.

The composition of the eluent is as follows:

solvent A: 0.025% trifluoroacetic acid (TFA) in water

solvent B: 0.025% TFA in acetonitrile.

Gradient: the percentage of solvent B varies from 0 to 100% in 2 minuteswith a plateau at 100% of B for 1 minute.

UV detection is carried out between 210 nm and 400 nm and mass detectionin chemical ionization mode at atmospheric pressure.

For interpreting the nuclear magnetic resonance (NMR) spectra thefollowing abbreviations are used: s: singlet; d: doublet; m: unresolvedmultiplet; bs: broad singlet; dd: doublet of a doublet.

Preparation 1.1

-   (IIa) : R₃, R₄, R₅=4-Cl; R₆, R₇, R₈=2,4-diCl. Methyl    4-2″,4″-trichloro[1,1′;2′,1″]terphenyl-4′-carboxylate.

A) 4-Hydroxy-3-iodobenzoic Acid

30 g of 4-hydroxybenzoic acid are placed in 780 ml of water containing18 g of sodium hydroxide, 49.5 g of sodium iodide are added, 675 ml of3.5% sodium hypochlorite solution are run in slowly and the mixture isleft with stirring at AT for 13 hours. 60 ml of concentrated H₂SO₄ areadded and then, after cooling, the precipitate formed is filtered offand washed with water. This gives 32.46 g of the expected compound,m.p.=163° C.

B) Methyl 4-hydroxy-3-iodobenzoate

32.46 g of the acid obtained in the preceding step is placed in amixture containing 138 ml of methanol and 10.36 ml of concentratedsulfuric acid and the mixture is heated at reflux for 3 and a halfhours. The solvent is concentrated under vacuum and the residue is takenup in demineralized water and ethyl ether. It is neutralized with Na₂CO₃and then the aqueous phase is extracted with AcOEt. The extract iswashed with water and then with a saturated NaCl solution. This gives 32g of the expected compound.

C) Methyl 2′,4′-dichloro-6-hydroxy-(1,1′-biphenyl)-carboxylate

5.6 g of methyl 4-hydroxy-3-iodobenzoate are introduced under argon into50 ml of anhydrous DMF and then 4.2 g of 2,4-dichlorophenylboronic acidand 5.54 ml of triethylamine and then 240 mg of tri-orthotolylphosphineare added and the mixture is left under argon for 1 hour. 180 mg ofpalladium acetate are added and then the mixture is heated at 100° C.for 4 hours. 2 g of 2,4-dichlorophenylboronic acid, 5.54 ml oftriethylamine, 120 mg of tri-orthotolylphoshine and 180 mg of palladiumacetate are added and then the mixture is heated at 100° C. for 8 hours.It is concentrated under vacuum and the residue is taken up in AcOEt andthen washed with 10% NH₄OH solution. Extraction is carried out withAcOEt and the extract is washed with water and then with saturated NaClsolution. The residue is dried and then chromatographed on silica,eluting with a cyclohexane/AcOEt mixture (82/18; v/v), to give 3.4 g ofthe expected compound.

D) Methyl2′,4′-dichloro-6-((trifluoromethyl-sulfonyl)oxy)(1,1′-biphenyl)-3-carboxylate

3.27 g of the compound obtained in the preceding step are placed in 150ml of pyridine, the mixture is cooled to between 0° C. and 5° C. and 2.8ml of triflic anhydride are run in dropwise. The mixture is maintainedwith stirring at AT overnight and then concentrated to dryness. Theresidue is chromatographed on silica, eluting with a cyclohexane/AcOEtmixture (90/10; v/v), to give 3.2 g of the expected compound.

E) Methyl 4,2″,4″-trichloro[1,1′;2′,1″]terphenyl-4′-carboxylate

3.2 g of the compound obtained in the preceding step are placed in 75 mlof toluene and 2.33 g of 4-chlorophenylboronic acid are added and then1.55 g of potassium carbonate. The mixture is left under argon for 30minutes and then 1.38 g of tetrakis(triphenylphosphine)palladium areadded and the reaction mixture is heated at between 80° C. and 85° C.for 3 hours. It is left overnight at AT and then diluted with AcOEt andwashed with 5% Na₂CO₃ solution (twice) and then with saturated NaClsolution. It is dried and then the residue is chromatographed on silicawith a cyclohexane/AcOEt mixture (80/20; v/v) to give 1.83 g of theexpected compound, which crystallizes from isopropyl ether, m.p.=136° C.

The procedure described above is used to prepare the methyl esters ofthe acids of formula (II) collated in the table below. TABLE 1 (IIa)

Preparations R₃, R₄, R₅ R₆, R₇, R₈ m.p. ° C./NMR 1.2 4-Cl 4-Cl 223° C.1.3 4-F 2,4-diCl NMR(DMSO-d₆) δ ppm: 6.9: m: 4H; 7.25: d: 1H; 7.35: dd:1H; 7.55; m: 2H; 7.80: d: 1H; 8.00: dd: 1H; 13.20: bs: 1H 1.4 4-CF₃2,4-diCl 206° C.

EXAMPLE 1 Compound I

4,2″,4″-Trichloro(N-1-piperidinyl)[1,1′;2′,1″]-terphenyl-4′carboxamide.

R₈=2,4-diCl

A) 4,2″,4″-Trichloro[1,1,′;2′,1″]terphenyl-4′-carboxylic acid

1.33 g of the compound from Preparation 1.1 is suspended in 30 ml ofethanol, 0.95 g of potassium hydroxide in solution in 5 ml of water isadded and the mixture is heated at reflux for 2 hours. After cooling toAT it is filtered over C{acute over (e )}lite® and concentrated todryness under vacuum. The residue is taken up in 30 ml of water and thenacidified to a pH of 1 by adding 1N HCl. The mixture is cooled using anice bath and then extracted with AcOEt. It is washed with water and thenwith saturated NaCl solution to give 1.22 g of the expected compound,m.p.=237° C.

B) 4,2″,4″-Trichloro[1,1′;2′,1″]terphenyl-4′-carboxylic chloride

500 mg of the acid obtained in the preceding step are suspended in 50 mlof toluene, 0.3 ml of thionyl chloride is added and the mixture isheated at reflux for 2 hours. The solvent is concentrated twice to give0.52 g of the expected compound in solid form.

C) 4,2″,4″-Trichloro(N-1-piperidinyl)[1,1′;2′,1″]-terphenyl-4′-carboxamide

A solution containing 0.17 ml of aminopiperidine and 0.22 ml oftriethylamine in 10 ml of DCM is prepared, this solution is cooled tobetween 0° C. and 5° C. and 0.52 g of the acid chloride obtained in thepreceding step in 10 ml of DCM is added dropwise. The mixture is left at+4° C. for 2 days. It is poured into ice-water, then extracted with DCMand washed with 5% Na₂CO₃ solution and then with saturated NaClsolution. The extracts are dried and then the residue is chromatographedon silica, eluting with a toluene/AcOEt mixture (88/12; v/v). This gives0.3 g of the expected compound, m.p.=182° C.

The procedure of Example 1 is used to prepare the compounds of theinvention which are described below. TABLE 2 (I)

Compounds R₁ R₂ R₃, R₄, R₅ R₆, R₇, R₈ Characterization 1 H

4-Cl 2,4-diCl m.p. = 182° C. 2 H

4-Cl 4-Cl m.p. = 233° C. 3 H

4-Cl 2,4-diCl m.p. = 98° C. 4 H

4-Cl 2,4-diCl m.p. = 168° C. 5 H

4-F 2,4-diCl m.p. = 175° C. 6 H

4-CF₃ 2,4-diCl m.p. = 177° C. 7 H

4-Cl 4-Cl M⁺ = 489.49 t = 1.95 8 H

4-Cl 4-Cl M⁺ = 484.95 t = 2.33 9 H

4-Cl 4-Cl M⁺ = 492.15 t = 2.28 10 H

4-Cl 4-Cl M⁺ = 411.98 t = 2.43 11 H

4-Cl 4-Cl M⁺ = 450.50 t = 2.43 12 —NR₁R₂

4-Cl 4-Cl M⁺ = 514.42 t = 2.50

1. Compounds of formula:

in which: R₁ represents hydrogen or a (C₁-C₄)alkyl; R₂ represents: a(C₃-C₇)alkyl group, an indan-1-yl or 1,2,3,4-tetrahydronaphthalen-1-ylgroup, said groups being unsubstituted or substituted by a halogen atomand/or a methyl group; a saturated, single-nitrogen heterocyclic radicalof 5 to 7 atoms, the nitrogen atom being substituted by a (C₁-C₄)alkyl,benzyl, (C₁-C₃)alkoxycarbonyl or (C₁-C₄)alkanoyl group; a group NR₉R₁₀;a group (CH₂)_(n)R₁₁, CH(CH₃)R₁₁, (CH₂)_(m)N(CH₃)R₁₁; a C₃-C₁₂nonaromatic carbocyclic radical, unsubstituted or substituted one ormore times by a methyl group; or R₁ and R₂ together with the nitrogenatom to which they are attached form either a piperazin-1-yl radicalsubstituted in position 4 by a phenyl or benzyl group, or apiperidin-1-yl radical disubstituted in position 4 by a phenyl or benzylgroup and by a (C₁-C₄)alkyl or (C₁-C₃)alkanoyl group; the phenyl orbenzyl group substituents on the piperazin-1-yl radical or thepiperidin-1-yl radical being unsubstituted or substituted by a halogenatom and/or a methyl group; R₃, R₄, R₅, R₆, R₇ and R₈ represent eachindependently of one another a hydrogen or halogen atom or a(C₁-C₆)alkyl, (C₁-C₆)alkoxy or trifluoromethyl group; R₉ and R₁₀together with the nitrogen atom to which they are attached form asaturated or unsaturated heterocyclic radical of 5 to 10 atomscontaining or not containing a second heteroatom selected from O and N,said radical being unsubstituted or substituted one or more times by a(C₁-C₄)alkyl, hydroxyl or (C₁-C₄)alkoxy group; R₁₁ represents: a phenylwhich is unsubstituted or substituted by one or more substituentsselected from a halogen atom and a methyl group; a heteroaryl radical of6 to 10 atoms containing one or more nitrogen atoms; n represents 1, 2or 3; m represents 0, 2 or 3; and their salts, their solvates and theirhydrates.
 2. A compound according to claim 1 of formula (I) in which: R₁represents a hydrogen atom or a (C₁-C₄)alkyl group; R₂ represents agroup NR₉R₁₀ or a nonaromatic C₃-C₁₂ carbocyclic radical which isunsubstituted or substituted one or more times by a methyl group; R₃,R₄, R₅, R₆, R₇ and R₈ represent each independently of one another ahydrogen or halogen atom or a (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl group; R₉ and R₁₀ together with the nitrogen atom towhich they are attached form a saturated or unsaturated heterocyclicradical of 5 to 10 atoms, containing or not containing a secondheteroatom selected from O and N, said radical being unsubstituted orsubstituted one or more times by a (C₁-C₄)alkyl group; and their salts,their solvates and their hydrates.
 3. A compound according to claim 1 offormula (I) in which: R₁ represents a hydrogen atom; and/or R₂represents a group selected from piperidin-1-yl, pyrrolidin-1-yl,cyclohexyl, spiro[5.5]undecanyl and1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl; and/or at least one of thesubstituents R₃, R₄ and R₅ represents a halogen atom or atrifluoromethyl group; and/or at least one of the substituents R₆, R₇and R₈ represents a halogen atom.
 4. A process for preparing a compoundof formula (I) according to claim 1 wherein a functional derivative ofterphenylic acid of formula:

in which R₃, R_(4,) R₅, R_(6,) R₇ and R₈ are as defined for a compoundof formula (I) in claim 1 is treated with an amine of formula HNR₁R₂(III) in which R₁ and R₂ are as defined for a compound of formula (I) inclaim
 1. 5. Compounds of formula:

in which R₃, R_(4,) R₅, R₆, R₇ and R₈ are as defined for a compound offormula (I) in claim 1 and R represents a hydrogen atom or a(C₁-C₄)alkyl group, on condition that R₃, R_(4,) R₅, R₆, R₇ and R₈ arenot simultaneously hydrogen, and on condition that, when R_(4,) R₅, R₇and R₈ represent hydrogen, R₃ and R₆ do not simultaneously represent afluorine atom in meta position, or a methoxy group in meta or paraposition, and on condition that when R₅ and R₈ represent hydrogen R₃, R₄and R₅, R₆ do not simultaneously represent 3,4-dimethoxy groups.
 6. Acompound according to claim 5 of formula (IIa) in which: R₃ is inposition 4 and represents a halogen atom or a trifluoromethyl group; R₆is in position 2 and represents a hydrogen or halogen atom; R₇ is inposition 4 and represents a halogen atom; R₄, R₅ and R₈ are hydrogen. 7.(canceled)
 8. A pharmaceutical composition which comprises a compound offormula (I) according to claim 1, or one of its pharmaceuticallyacceptable salts, hydrates or solvates, and at least onepharmaceutically acceptable excipient.
 9. A method for treating anydisease involving the CB₁ cannabinoid receptor which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 1. 10. A method for treating psychoticdisorders, memory and cognitive disorders, appetite disorders andobesity, or for tobacco withdrawal or alcohol withdrawal which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 1. 11. A compound according to claim 2of formula (I) in which: R₁ represents a hydrogen atom or a (C₁-C₄)alkylgroup; R₂ represents a group NR₉R₁₀ or a nonaromatic C₃-C₁₂ carbocyclicradical which is unsubstituted or substituted one or more times by amethyl group; R₃, R_(4,) R₅, R₆, R₇ and R₈ represent each independentlyof one another a hydrogen or halogen atom or a (C₁-C₆)alkyl,(C₁-C₆)alkoxy or trifluoromethyl group; R₉ and R₁₀ together with thenitrogen atom to which they are attached form a saturated or unsaturatedheterocyclic radical of 5 to 10 atoms, containing or not containing asecond heteroatom selected from O and N, said radical beingunsubstituted or substituted one or more times by a (C₁-C₄)alkyl group;and their salts, their solvates and their hydrates.
 12. A pharmaceuticalcomposition which comprises a compound of formula (I) according to claim2 or one of its pharmaceutically acceptable salts, hydrates or solvates,and at least one pharmaceutically acceptable excipient.
 13. Apharmaceutical composition which comprises a compound of formula (I)according to claim 3 or one of its pharmaceutically acceptable salts,hydrates or solvates, and at least one pharmaceutically acceptableexcipient.
 14. A pharmaceutical composition which comprises a compoundof formula (I) according to claim 11 or one of its pharmaceuticallyacceptable salts, hydrates or solvates, and at least onepharmaceutically acceptable excipient.
 15. A method for treating anydisease involving the CB₁ cannabinoid receptor which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 2. 16. A method for treating anydisease involving the CB₁ cannabinoid receptor which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 3. 17. A method for treating anydisease involving the CB₁ cannabinoid receptor which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 11. 18. A method for treating psychoticdisorders, memory and cognitive disorders, appetite disorders andobesity, or for tobacco withdrawal or alcohol withdrawal which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 2. 19. A method for treating psychoticdisorders, memory and cognitive disorders, appetite disorders andobesity, or for tobacco withdrawal or alcohol withdrawal which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 3. 20. A method for treating psychoticdisorders, memory and cognitive disorders, appetite disorders andobesity, or for tobacco withdrawal or alcohol withdrawal which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim 11.